Structure-function analysis of oncogenic EGFR Kinase Domain Duplication reveals insights into activation and a potential approach for therapeutic targeting
Zhenfang Du,Benjamin P. Brown,Soyeon Kim,Donna C. Ferguson,Dean Pavlick,Gowtham Jayakumaran,Ryma Benayed,Jean-Nicolas Gallant,Yun-Kai Zhang,Yingjun Yan,Monica Red-Brewer,Siraj M. Ali,Alexa B. Schrock,Ahmet Zehir,Marc Ladanyi,Adam W. Smith,Jens Meiler,Christine M. Lovly +17 more
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In this paper, the prevalence of ERBB family KDDs across multiple human cancers and evaluate the functional biochemistry of EGFR-KDD as it relates to pathogenesis and potential therapeutic intervention.Abstract:
Mechanistic understanding of oncogenic variants facilitates the development and optimization of treatment strategies. We recently identified in-frame, tandem duplication of EGFR exons 18 - 25, which causes EGFR Kinase Domain Duplication (EGFR-KDD). Here, we characterize the prevalence of ERBB family KDDs across multiple human cancers and evaluate the functional biochemistry of EGFR-KDD as it relates to pathogenesis and potential therapeutic intervention. We provide computational and experimental evidence that EGFR-KDD functions by forming asymmetric EGF-independent intra-molecular and EGF-dependent inter-molecular dimers. Time-resolved fluorescence microscopy and co-immunoprecipitation reveals EGFR-KDD can form ligand-dependent inter-molecular homo- and hetero-dimers/multimers. Furthermore, we show that inhibition of EGFR-KDD activity is maximally achieved by blocking both intra- and inter-molecular dimerization. Collectively, our findings define a previously unrecognized model of EGFR dimerization, providing important insights for the understanding of EGFR activation mechanisms and informing personalized treatment of patients with tumors harboring EGFR-KDD. Finally, we establish ERBB KDDs as recurrent oncogenic events in multiple cancers.read more
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EGFR in Cancer: Signaling Mechanisms, Drugs, and Acquired Resistance
TL;DR: The epidermal growth factor receptor (EGFR) has served as the founding member of the large family of growth factor receptors harboring intrinsic tyrosine kinase function as discussed by the authors.
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TL;DR: In this article, a review focused on how curcumin exhibits anti-cancer effects through inhibition of RTKs and downstream signalling pathways like the MAPK, PI3K/Akt, JAK/STAT and NF-κB pathways.
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Xmrks the Spot: Fish Models for Investigating Epidermal Growth Factor Receptor Signaling in Cancer Research.
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Allele-specific activation, enzyme kinetics, and inhibitor sensitivities of EGFR exon 19 deletion mutations in lung cancer
Benjamin P. Brown,Yun-Kai Zhang,Soyeon Kim,P Finneran,Yingjun Yan,Zhenfang Du,Jiyoon Kim,Abigail Leigh Hartzler,Michele LeNoue-Newton,Adam W. Smith,Jens Meiler,Christine M. Lovly +11 more
TL;DR: Functional differences between distinct EGFR ex19del variants attributable to recurring sequence and structure motifs are described and proposed, suggesting a possible explanation for observed differences in patient outcomes stratified by ex 19del subtype and reinforcing the need for allele-specific considerations in clinical treatment decision making.
References
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The Somatic Genomic Landscape of Glioblastoma
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